Cathepsin S is a member of the papain superfamily of cysteine proteases which also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays a key role in the processing of invariant chain in MHC class II complexes allowing the complex to associate with antigenic peptides. MHC class II complexes are then transported to the surface of the cell for presentation to effector cells such as T cells. The process of antigen presentation is a fundamental step in initiation of the immune response. In this respect inhibitors of cathepsin S could be useful agents in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cathepsin S has also been implicated in a variety of other diseases involving extracellular proteolysis such as the development of emphysema in COPD through degradation of elastin and in Alzheimers disease.
Other Cathepsins notably K and L have been shown to degrade bone collagen and other bone matrix proteins. Inhibitors of these cysteine proteases would be expected to be useful in the treatment of diseases involving bone resorption such as osteoporosis.
The present invention therefore provides a compound of formula (I)
R1 is independently hydrogen, C1-6alkyl or C3-6 cycloalkylR2 is independently aryl, heteroaryl or a group C1-6alkylR9, CO(C1-6alkyl)R9 or SO2(C1-6alkyl)R9; where R9 is aryl or heteroarylor R1 and R2 together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated ring optionally containing a carbonyl group, O, S or N atom and optionally substituted by one or more C1-6alkyl, amino, hydroxy, CO2C1-6alkyl, COC1-6alkyl, halogen, C1-6alkylhydroxy, NR10R11 where R10 and R11 are independently hydrogen, C1-6alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR1 group, C1-6alkylNR12R13 where R12 and R13 are independently hydrogen or C1-6alkyl, CONR12R13, or optionally substituted by C1-6alkylR9, aryl, phenoxy, COaryl, COheteroaryl or a heteroaryl group, the latter six groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR12R13, SO2NR12R13, SO2R12, trifluoromethyl, NHSO2R12, NHCOR12, ethylenedioxy, methylenedioxy, C1-6alkyl, C1-6alkoxy, C1-6 alkyl NR10R11, SR12 or NR10R11;Het is a heteroaryl ring chosen from pyridine, pyrimidine, pyrazine, pyridazine or triazine and optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR12R13, SO2NR12R13, SO2R12, trifluoromethyl, NHSO2R12, NHCOR12, C1-6alkyl, C1-6alkoxy, SR12 or NR10R11;R3 is independently hydrogen, C1-6alkyl or C3-6cycloalkyl;R4 is independently hydrogen, C1-8alkyl, C3-8cycloalkyl, arylC1-5alkyl or heteroarylC1-5alkyl, the latter three groups being optionally substituted by one or more halogen, amino, hydroxy, C1-6alkyl, C1-6alkoxy, SR12 or NR10R11;R5 is independently hydrogen, C1-6alkyl or C3-6cycloalkyl;R6 is independently hydrogen, C1-6alkyl or C3-6cycloalkyl;R7 is independently hydrogen, C1-6alkyl or C3-6cycloalkyl;R8 is independently hydrogen, aryl, heteroaryl or C1-6alkyl optionally substituted with one or more aryl, heteroaryl, halogen, amino, hydroxy, carboxy, CONR12R13, SO2NR12R13, SO2R12, NHSO2R12, NHCOR12, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, SR12 or NR10R11;or a pharmaceutically acceptable salt thereof.
Aryl groups include phenyl and naphthyl. Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fused heterocyclic rings containing one or more heteroatoms selected from N, S or O. Examples include pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazole, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, benzothienyl and indolyl.
Aryl and heteroaryl groups can be optionally substituted by on or more of the following groups; halogen, amino, hydroxy, cyano, nitro, carboxy, CONR12R13, SO2NR12R13, SO2R12, trifluoromethyl, NHSO2R12, NHCOR12, ethylenedioxy, methylenedioxy, C1-6alkyl, C1-6alkoxy, C1-6alkyl NR10R11, SR12 or NR10R11.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Preferably R1 is hydrogen or C1-6alkyl, more preferably methyl and R2 is CH2R9 or CH2CH2R9 where R9 is phenyl or a 5- or 6-membered aromatic ring containing one or two heteroatoms and optionally substituted by C1-6alkyl. More preferably R2 is CH2R9 or CH2CH2R9 where R9 is phenyl, pyridyl or oxazole substituted by methyl.
Alternatively R1 and R2 form a piperidine, piperazine, pyrrolidine, morpholine, or thiomorpholine ring optionally substituted by CH2OH, CH2CH2OH, hydroxy, CONH2, phenyl, phenoxy, C(O)-furyl, the latter three groups being optionally substituted by halogen, in particular chloro.
Preferably Het is pyrimidine ring.
Preferably R3 is hydrogen.
Preferably R4 is hydrogen.
Preferably R5 is C1-6alkyl, more preferably iso-butyl.
Preferably R6 is hydrogen.
Preferably R7 and R8 are both hydrogen.
Preferred compounds of the invention include:    N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide    N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-piperazin-1-ylpyrimidin-4-yl)-L-leucinamide,    N-[Cyano(2-methoxyphenyl)methyl]-N-(2-morpholin-4-ylpyrimidin-4-yl)-L-phenylalaninamide    N˜1˜-[Cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-alaninamide    N-[2-(Benzylamino)pyrimidin-4-yl]-N-(cyanomethyl)-L-phenylalaninamide    N-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide    N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide    N˜2˜-[2-(Benzylamino)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide    N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide    N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide    N˜1˜-(Cyanomethyl)-N˜2˜-(4-morpholin-4-ylpyrimidin-2-yl)-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxy-4-phenylpiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide    N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide    N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide,    N˜2˜-{2-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide,    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(thien-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-(2-thiomorpholin-4-ylpyrimidin-4-yl)-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[2-(hydroxymethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-4-yl}-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-furoyl)piperazin-1-yl]pyrimidin-4-yl}-L-leucinamide,    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(2-pyridin-2-ylethyl)amino]pyrimidin-4-yl}-L-leucinamide    N˜2˜-[2-(4-Benzylpiperidin-1-yl)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-pyridin-2-ylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-hydroxyethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide    N˜2˜-{2-[4-(3-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenoxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-[2-(3-phenylpyrrolidin-1-yl)pyrimidin-4-yl]-L-leucinamide    N˜1˜-(Cyanomethyl)-N˜2˜-(2-{methyl[(3-methylisoxazol-5-yl)methyl]amino}pyrimidin-4-yl)-L-leucinamideand pharmaceutically acceptable salts thereof.
The present invention further provides a process for the preparation of a compound of formula (I) which comprises                (i) reaction of a compound of general formula (II)        
wherein L represents a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement. An oxidising agent such as a peracid may be used, for example meta-chloroperbenzoic acid in dichloromethane at room temperature.
L may be displaced by NR1R2 respectively where R1 and R2 are defined in formula (I). The reaction may be performed in an inert solvent for example dioxane, N,N-dimethylformamide at ambient temperature or with heating, usually with a base present for example N,N-diisopropylethylamine.
X may be CN, or a group that can be readily converted into a nitrile, for example C1-6alkoxycarbonyl, CONH2 or CO2H.

Compounds of formula (II) may be prepared from compounds of formula (III) by displacement of a leaving group L1 from compounds of formula (IV).
Wherein L1 represents a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement. An oxidising agent such as a peracid may be used, for example meta-chloroperbenzoic acid in dichloromethane at room temperature. The reaction may be performed in an inert solvent for example dioxane, N,N-dimethylformamide at ambient temperature or with heating, usually with a base present for example N,N-diisopropylethylamine.
Compounds of formula (III) may be prepared from the reaction of compounds of formula (V) with compounds of formula (VI) using an appropriate coupling agent, for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, carbonyl diimidazole. Alternatively the acid may be activated by formation of the acid chloride using for example, oxalyl chloride.

P is a nitrogen protecting group for example tert-butylcarbamate, benzyl carbamate, benzyl.
Compound of general formula (II) may also be prepared from the reaction of compounds of formula (VII) with compounds of formula (VI) using an appropriate coupling agent, for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, carbonyl diimidazole. Alternatively the acid may be activated by formation of the acid chloride using for example, oxalyl chloride.
                (ii) reaction of a compound of general formula (VII) with compounds of formula (III) or reaction of a compound of general formula (IX) with a compound of general formula (VI).        

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent.
According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain. Preferably the compounds of the invention are used to treat pain, especially neuropathic pain.
The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man.
In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg−1 to 100 mgkg−1 of the compound, preferably in the range of 5 mgkg−1 to 20 mgkg−1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:
(a)Tablet Img/tabletCompound X.100Lactose Ph.Eur.179Croscarmellose sodium12.0Polyvinylpyrrolidone6Magnesium stearate3.0(b)Tablet IImg/tabletCompound X50Lactose Ph.Eur.229Croscarmellose sodium12.0Polyvinylpyrrolidone6Magnesium stearate3.0(c)Tablet IIImg/tabletCompound X1.0Lactose Ph.Eur.92Croscarmellose sodium4.0Polyvinylpyrrolidone2.0Magnesium stearate1.0(d)Capsulemg/capsuleCompound X10Lactose Ph.Eur.389Croscarmellose sodium100Magnesium stearate1.(e)Injection I(50 mg/ml)Compound X5.0% w/vIsotonic aqueous solutionto 100%
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
The following examples illustrate the invention.